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- EMDB-21618: CryoEM structure of full-length ZIKV NS5-hSTAT2 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-21618
TitleCryoEM structure of full-length ZIKV NS5-hSTAT2 complex
Map data
Sample
  • Complex: full-length ZIKV NS5-hSTAT2 complex
    • Complex: hSTAT2
      • Protein or peptide: Signal transducer and activator of transcription 2
    • Complex: ZIKV NS5
      • Protein or peptide: Non-structural protein 5
  • Ligand: ZINC ION
KeywordsZIKV NS5 / hSTAT2 / CryoEM / IMMUNE SYSTEM
Function / homology
Function and homology information


ISGF3 complex / symbiont-mediated suppression of host interferon-mediated signaling pathway / Interleukin-20 family signaling / negative regulation of type I interferon-mediated signaling pathway / type I interferon-mediated signaling pathway / regulation of mitochondrial fission / ubiquitin-like protein ligase binding / Regulation of IFNA/IFNB signaling / regulation of protein phosphorylation / flavivirin ...ISGF3 complex / symbiont-mediated suppression of host interferon-mediated signaling pathway / Interleukin-20 family signaling / negative regulation of type I interferon-mediated signaling pathway / type I interferon-mediated signaling pathway / regulation of mitochondrial fission / ubiquitin-like protein ligase binding / Regulation of IFNA/IFNB signaling / regulation of protein phosphorylation / flavivirin / cell surface receptor signaling pathway via JAK-STAT / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / ribonucleoside triphosphate phosphatase activity / defense response / Evasion by RSV of host interferon responses / response to peptide hormone / RNA polymerase II transcription regulator complex / Interferon alpha/beta signaling / viral capsid / double-stranded RNA binding / regulation of cell population proliferation / nucleoside-triphosphate phosphatase / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / symbiont-mediated suppression of host toll-like receptor signaling pathway / protein-macromolecule adaptor activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / defense response to virus / clathrin-dependent endocytosis of virus by host cell / Potential therapeutics for SARS / methyltransferase cap1 activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / host cell cytoplasm / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA helicase activity / protein dimerization activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host innate immune response / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA polymerase II cis-regulatory region sequence-specific DNA binding / symbiont entry into host cell / DNA-binding transcription factor activity / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / serine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / fusion of virus membrane with host endosome membrane / lipid binding / viral envelope / regulation of transcription by RNA polymerase II / GTP binding / chromatin / virion attachment to host cell / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / virion membrane / structural molecule activity / positive regulation of transcription by RNA polymerase II / ATP hydrolysis activity / proteolysis / extracellular region / nucleoplasm / ATP binding / metal ion binding / identical protein binding / nucleus / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Signal transducer and activation of transcription 2, C-terminal / STAT2, SH2 domain / Signal transducer and activator of transcription 2 C terminal / STAT transcription factor, DNA-binding, N-terminal / STAT transcription factor, protein interaction / STAT transcription factor, all-alpha domain / STAT transcription factor, DNA-binding / : / STAT transcription factor, coiled-coil domain / STAT protein, DNA binding domain ...Signal transducer and activation of transcription 2, C-terminal / STAT2, SH2 domain / Signal transducer and activator of transcription 2 C terminal / STAT transcription factor, DNA-binding, N-terminal / STAT transcription factor, protein interaction / STAT transcription factor, all-alpha domain / STAT transcription factor, DNA-binding / : / STAT transcription factor, coiled-coil domain / STAT protein, DNA binding domain / STAT protein, protein interaction domain / Signal transducer and activator of transcription, linker domain / STAT protein, protein interaction domain / STAT transcription factor, N-terminal domain superfamily / Transcription factor STAT / STAT transcription factor, coiled coil / p53-like transcription factor, DNA-binding / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C superfamily / Genome polyprotein, Flavivirus / : / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / Flavivirus NS2B domain profile. / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus non-structural protein NS2A / Flavivirus non-structural protein NS2A / Flavivirus NS3, petidase S7 / Peptidase S7, Flavivirus NS3 serine protease / Flavivirus NS3 protease (NS3pro) domain profile. / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / RNA-directed RNA polymerase, flavivirus / Flavivirus RNA-directed RNA polymerase, fingers and palm domains / Flavivirus capsid protein C / Flavivirus capsid protein C / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS1 / Envelope glycoprotein M, flavivirus / Envelope glycoprotein M superfamily, flavivirus / Flavivirus envelope glycoprotein M / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flavivirus polyprotein propeptide / Flavivirus envelope glycoprotein E, stem/anchor domain / : / Flavivirus NS3 helicase, C-terminal helical domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein E, immunoglobulin-like domain / Flavivirus glycoprotein, immunoglobulin-like domain / Flavivirus glycoprotein central and dimerisation domain / Flavivirus glycoprotein, central and dimerisation domains / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Ribosomal RNA methyltransferase, FtsJ domain / FtsJ-like methyltransferase / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flaviviral glycoprotein E, dimerisation domain / DEAD box, Flavivirus / Flavivirus DEAD domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / helicase superfamily c-terminal domain / Immunoglobulin E-set / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Signal transducer and activator of transcription 2 / Genome polyprotein
Similarity search - Component
Biological speciesHomo sapiens (human) / Zika virus
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsBoxiao W / Stephanie T
Funding support United States, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Library of Medicine (NIH/NLM)1S10RR23057 United States
National Institutes of Health/National Library of Medicine (NIH/NLM)1S10OD018111 United States
National Institutes of Health/National Library of Medicine (NIH/NLM)1R35GM119721 United States
National Science Foundation (NSF, United States)DBI-1338135 United States
National Institutes of Health/National Library of Medicine (NIH/NLM)1R21AI147057 United States
CitationJournal: Nat Struct Mol Biol / Year: 2020
Title: Structural basis for STAT2 suppression by flavivirus NS5.
Authors: Boxiao Wang / Stephanie Thurmond / Kang Zhou / Maria T Sánchez-Aparicio / Jian Fang / Jiuwei Lu / Linfeng Gao / Wendan Ren / Yanxiang Cui / Ethan C Veit / HeaJin Hong / Matthew J Evans / ...Authors: Boxiao Wang / Stephanie Thurmond / Kang Zhou / Maria T Sánchez-Aparicio / Jian Fang / Jiuwei Lu / Linfeng Gao / Wendan Ren / Yanxiang Cui / Ethan C Veit / HeaJin Hong / Matthew J Evans / Seán E O'Leary / Adolfo García-Sastre / Z Hong Zhou / Rong Hai / Jikui Song /
Abstract: Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy that viruses use to establish infections, yet the detailed mechanism remains elusive, owing to a lack of ...Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy that viruses use to establish infections, yet the detailed mechanism remains elusive, owing to a lack of structural information about the viral-cellular complex involved. Here, we report the cryo-EM and crystal structures of human STAT2 (hSTAT2) in complex with the non-structural protein 5 (NS5) of Zika virus (ZIKV) and dengue virus (DENV), revealing two-pronged interactions between NS5 and hSTAT2. First, the NS5 methyltransferase and RNA-dependent RNA polymerase (RdRP) domains form a conserved interdomain cleft harboring the coiled-coil domain of hSTAT2, thus preventing association of hSTAT2 with interferon regulatory factor 9. Second, the NS5 RdRP domain also binds the amino-terminal domain of hSTAT2. Disruption of these ZIKV NS5-hSTAT2 interactions compromised NS5-mediated hSTAT2 degradation and interferon suppression, and viral infection under interferon-competent conditions. Taken together, these results clarify the mechanism underlying the functional antagonism of STAT2 by both ZIKV and DENV.
History
DepositionMar 31, 2020-
Header (metadata) releaseJul 8, 2020-
Map releaseJul 8, 2020-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6wcz
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21618.png

Downloads & links

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Map

FileDownload / File: emd_21618.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.025 / Movie #1: 0.025
Minimum - Maximum-0.065448426 - 0.14940508
Average (Standard dev.)0.000026761094 (±0.0046450943)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.92 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.071.071.07
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z273.920273.920273.920
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0650.1490.000

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Supplemental data

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Sample components

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Entire : full-length ZIKV NS5-hSTAT2 complex

EntireName: full-length ZIKV NS5-hSTAT2 complex
Components
  • Complex: full-length ZIKV NS5-hSTAT2 complex
    • Complex: hSTAT2
      • Protein or peptide: Signal transducer and activator of transcription 2
    • Complex: ZIKV NS5
      • Protein or peptide: Non-structural protein 5
  • Ligand: ZINC ION

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Supramolecule #1: full-length ZIKV NS5-hSTAT2 complex

SupramoleculeName: full-length ZIKV NS5-hSTAT2 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Molecular weightTheoretical: 141 kDa/nm

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Supramolecule #2: hSTAT2

SupramoleculeName: hSTAT2 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: ZIKV NS5

SupramoleculeName: ZIKV NS5 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Zika virus

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Macromolecule #1: Signal transducer and activator of transcription 2

MacromoleculeName: Signal transducer and activator of transcription 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 98.025031 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: MAQWEMLQNL DSPFQDQLHQ LYSHSLLPVD IRQYLAVWIE DQNWQEAALG SDDSKATMLF FHFLDQLNYE CGRCSQDPES LLLQHNLRK FCRDIQPFSQ DPTQLAEMIF NLLLEEKRIL IQAQRAQLEQ GEPVLETPVE SQQHEIESRI LDLRAMMEKL V KSISQLKD ...String:
MAQWEMLQNL DSPFQDQLHQ LYSHSLLPVD IRQYLAVWIE DQNWQEAALG SDDSKATMLF FHFLDQLNYE CGRCSQDPES LLLQHNLRK FCRDIQPFSQ DPTQLAEMIF NLLLEEKRIL IQAQRAQLEQ GEPVLETPVE SQQHEIESRI LDLRAMMEKL V KSISQLKD QQDVFCFRYK IQAKGKTPSL DPHQTKEQKI LQETLNELDK RRKEVLDASK ALLGRLTTLI ELLLPKLEEW KA QQQKACI RAPIDHGLEQ LETWFTAGAK LLFHLRQLLK ELKGLSCLVS YQDDPLTKGV DLRNAQVTEL LQRLLHRAFV VET QPCMPQ TPHRPLILKT GSKFTVRTRL LVRLQEGNES LTVEVSIDRN PPQLQGFRKF NILTSNQKTL TPEKGQSQGL IWDF GYLTL VEQRSGGSGK GSNKGPLGVT EELHIISFTV KYTYQGLKQE LKTDTLPVVI ISNMNQLSIA WASVLWFNLL SPNLQ NQQF FSNPPKAPWS LLGPALSWQF SSYVGRGLNS DQLSMLRNKL FGQNCRTEDP LLSWADFTKR ESPPGKLPFW TWLDKI LEL VHDHLKDLWN DGRIMGFVSR SQERRLLKKT MSGTFLLRFS ESSEGGITCS WVEHQDDDKV LIYSVQPYTK EVLQSLP LT EIIRHYQLLT EENIPENPLR FLYPRIPRDE AFGCYYQEKV NLQERRKYLK HRLIVVSNRQ VDELQQPLEL KPEPELES L ELELGLVPEP ELSLDLEPLL KAGLDLGPEL ESVLESTLEP VIEPTLCMVS QTVPEPDQGP VSQPVPEPDL PCDLRHLNT EPMEIFRNCV KIEEIMPNGD PLLAGQNTVD EVYVSRPSHF YTDGPLMPSD F

UniProtKB: Signal transducer and activator of transcription 2

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Macromolecule #2: Non-structural protein 5

MacromoleculeName: Non-structural protein 5 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Zika virus
Molecular weightTheoretical: 103.118703 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: GGGTGETLGE KWKARLNQMS ALEFYSYKKS GITEVCREEA RRALKDGVAT GGHAVSRGSA KLRWLVERGY LQPYGKVVDL GCGRGGWSY YAATIRKVQE VRGYTKGGPG HEEPMLVQSY GWNIVRLKSG VDVFHMAAEP CDTLLCDIGE SSSSPEVEET R TLRVLSMV ...String:
GGGTGETLGE KWKARLNQMS ALEFYSYKKS GITEVCREEA RRALKDGVAT GGHAVSRGSA KLRWLVERGY LQPYGKVVDL GCGRGGWSY YAATIRKVQE VRGYTKGGPG HEEPMLVQSY GWNIVRLKSG VDVFHMAAEP CDTLLCDIGE SSSSPEVEET R TLRVLSMV GDWLEKRPGA FCIKVLCPYT STMMETMERL QRRHGGGLVR VPLSRNSTHE MYWVSGAKSN IIKSVSTTSQ LL LGRMDGP RRPVKYEEDV NLGSGTRAVA SCAEAPNMKI IGRRIERIRN EHAETWFLDE NHPYRTWAYH GSYEAPTQGS ASS LVNGVV RLLSKPWDVV TGVTGIAMTD TTPYGQQRVF KEKVDTRVPD PQEGTRQVMN IVSSWLWKEL GKRKRPRVCT KEEF INKVR SNAALGAIFE EEKEWKTAVE AVNDPRFWAL VDREREHHLR GECHSCVYNM MGKREKKQGE FGKAKGSRAI WYMWL GARF LEFEALGFLN EDHWMGRENS GGGVEGLGLQ RLGYILEEMN RAPGGKMYAD DTAGWDTRIS KFDLENEALI TNQMEE GHR TLALAVIKYT YQNKVVKVLR PAEGGKTVMD IISRQDQRGS GQVVTYALNT FTNLVVQLIR NMEAEEVLEM QDLWLLR KP EKVTRWLQSN GWDRLKRMAV SGDDCVVKPI DDRFAHALRF LNDMGKVRKD TQEWKPSTGW SNWEEVPFCS HHFNKLYL K DGRSIVVPCR HQDELIGRAR VSPGAGWSIR ETACLAKSYA QMWQLLYFHR RDLRLMANAI CSAVPVDWVP TGRTTWSIH GKGEWMTTED MLMVWNRVWI EENDHMEDKT PVTKWTDIPY LGKREDLWCG SLIGHRPRTT WAENIKDTVN MVRRIIGDEE KYMDYLSTQ VRYLGEEGST PGVL

UniProtKB: Genome polyprotein

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5 / Details: 25 mM Tris-HCl, pH 7.5, 175 mM NaCl, 5 mM DTT
GridMaterial: COPPER
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 48.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.0) / Number images used: 118760
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 2.0)
Final angle assignmentType: ANGULAR RECONSTITUTION

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